| Literature DB >> 34385691 |
Tetsuya Nagata1,2, Chrissa A Dwyer3, Kie Yoshida-Tanaka1,2, Kensuke Ihara1,2, Masaki Ohyagi1,2, Hidetoshi Kaburagi1,2, Haruka Miyata1,2, Satoe Ebihara1,2, Kotaro Yoshioka1,2, Takashi Ishii1,2, Kanjiro Miyata4, Kenichi Miyata5, Berit Powers3, Tomoko Igari5, Syunsuke Yamamoto5, Naoto Arimura5, Hideki Hirabayashi5, Toshiki Uchihara1, Rintaro Iwata Hara1,2,6, Takeshi Wada6, C Frank Bennett3, Punit P Seth3, Frank Rigo3, Takanori Yokota7,8.
Abstract
Achieving regulation of endogenous gene expression in the central nervous system (CNS) with antisense oligonucleotides (ASOs) administered systemically would facilitate the development of ASO-based therapies for neurological diseases. We demonstrate that DNA/RNA heteroduplex oligonucleotides (HDOs) conjugated to cholesterol or α-tocopherol at the 5' end of the RNA strand reach the CNS after subcutaneous or intravenous administration in mice and rats. The HDOs distribute throughout the brain, spinal cord and peripheral tissues and suppress the expression of four target genes by up to 90% in the CNS, whereas single-stranded ASOs conjugated to cholesterol have limited activity. Gene knockdown was observed in major CNS cell types and was greatest in neurons and microglial cells. Side effects, such as thrombocytopenia and focal brain necrosis, were limited by using subcutaneous delivery or by dividing intravenous injections. By crossing the blood-brain barrier more effectively, cholesterol-conjugated HDOs may overcome the limited efficacy of ASOs targeting the CNS without requiring intrathecal administration.Entities:
Mesh：
Substances：
Year: 2021 PMID： 34385691 DOI： 10.1038/s41587-021-00972-x
Source DB: PubMed Journal: Nat Biotechnol ISSN： 1087-0156 Impact factor: 68.164